CN102471302B - Preparation process of dronedarone and its salts - Google Patents
Preparation process of dronedarone and its salts Download PDFInfo
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- CN102471302B CN102471302B CN201180003259.6A CN201180003259A CN102471302B CN 102471302 B CN102471302 B CN 102471302B CN 201180003259 A CN201180003259 A CN 201180003259A CN 102471302 B CN102471302 B CN 102471302B
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- dronedarone
- solvent
- dronedarone hydrochloride
- preparing
- hydrochloride
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- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229960002084 dronedarone Drugs 0.000 title claims abstract description 38
- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title description 31
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 claims abstract description 65
- 229960002919 dronedarone hydrochloride Drugs 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 33
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 238000007670 refining Methods 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- 150000002576 ketones Chemical class 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 150000002825 nitriles Chemical group 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003637 basic solution Substances 0.000 claims description 7
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 235000010755 mineral Nutrition 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical group O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000005917 acylation reaction Methods 0.000 abstract description 8
- 239000000047 product Substances 0.000 abstract description 5
- 229940126062 Compound A Drugs 0.000 abstract description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 abstract 2
- SPIIBUQYWNFELT-UHFFFAOYSA-N (5-amino-2-butyl-1-benzofuran-3-yl)-[4-[3-(dibutylamino)propoxy]phenyl]methanone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(N)C=C12 SPIIBUQYWNFELT-UHFFFAOYSA-N 0.000 abstract 1
- 230000010933 acylation Effects 0.000 abstract 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 abstract 1
- 239000012043 crude product Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 238000010992 reflux Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 4
- 229960005260 amiodarone Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- XGAJABPTUOLUAE-UHFFFAOYSA-N 2-butyl-5-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=C2OC(CCCC)=CC2=C1 XGAJABPTUOLUAE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- GPEHQHXBPDGGDP-UHFFFAOYSA-N acetonitrile;propan-2-one Chemical compound CC#N.CC(C)=O GPEHQHXBPDGGDP-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- -1 methylsulfonyl compound Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Abstract
A process for preparing dronedarone or pharmaceutically acceptable salts thereof. The process comprises reacting 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl) benzofuran (compound A) with methanesulfonyl chloride without any catalyst to provide a crude dronedarone hydrochloride, which is purified to afford highly pure product. Then the dronedarone hydrochloride can be converted to highly pure dronedarone through dealing with alkaline solvent, which can be subsequently converted to other pharmaceutically acceptable salts thereof. In this process, acylation between compound A and methanesulfonyl chloride is carried out successfully and the dimethylsulfonyl by-product is inhibited.
Description
Technical field
The new preparation method who the present invention relates to 2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl)-5-sulfonyloxy methyl amido-cumarone (Dronedarone) and salt thereof, it is used for the treatment of the disease of cardiovascular systems.
Background technology
Dronedarone (SR33589) is benzofuran derivative, is the treatment antiarrhythmic medicament of recent development.Structure and feature and cardiovascular drug amiodarone are similar, and this medicine is not containing iodine, and lipotropy is lower.Dronedarone had both kept the curative effect of amiodarone, there is no again the outer untoward reaction of the heart of amiodarone, therefore promised to be saferly, and patient's tolerance is better, as treatment irregular pulse, substitutes one of medicine of amiodarone.Along with the continuous quickening of social modernization's process, the social pressures that people bear are increasing, and the quantity of China's cardiovascular patient is also in continuous increase, and cardiovascular disorder is listed in one of ten large causes of death.Therefore developing Dronedarone will bring good economic benefit and social benefit.The chemical structure of Dronedarone is suc as formula shown in I:
As described in scheme 1; document US5; 223; it is starting raw material that 510A be take 2-butyl-5-nitrobenzofuran; through acidylate, hydrolysis, O-hydrocarbonylation, reduction, made 5-amino-2-butyl 3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone (being called compd A in literary composition); compd A carries out acylation reaction with methylsulfonyl chloride under triethylamine catalysis, through column chromatography purification, has obtained Dronedarone.Then in ethyl acetate, obtained Dronedarone hydrochloride with hydrogenchloride-ether salify.
Scheme 1:
In the method, compd A and methylsulfonyl chloride carry out acylation reaction, are easy to generate two methylsulfonyl by products (being called formula Ia compound in literary composition), and it need to carry out purifying through the operation of this complexity of column chromatography, and this is very uneconomic for suitability for industrialized production.In addition, the preparation of Dronedarone hydrochloride needs salify operation, need to use more conversion unit, has reduced the yield of whole route simultaneously, has improved production cost.
Process for acylating research for amine is more; US5, has also reported in 223,510A under triethylamine catalysis; 5-amino-2-butyl-cumarone reacts with methylsulfonyl chloride and generates two methylsulfonyl compounds in tetracol phenixin; be Compound I I a, rather than obtain single methylsulfonyl compound, i.e. Compound I I; Compound I I a can be converted into Compound I I again through deacylated tRNA; but increase deacylated tRNA operation, to improving production cost, be also unfavorable for suitability for industrialized production equally.As shown in scheme 2:
Scheme 2:
Document WO03/048144A2 has reported the ratio of 2-butyl-5-cumarone amine Compound I Ia and Compound I I under different catalysts, draws the method for preparing Compound I I between 5 < Pka < 10.
US2005049302 discloses by 5-amino-2-butyl-cumarone and has prepared Compound I I subsequently, and mustn't go to the method for Compound I Ia.Synthetic Dronedarone (square case 3) is reacted in this invention under tin tetrachloride condition with compound III with Compound I I, the method yield is low, and still passes through the complicated operation stepss such as column chromatography purification, is unfavorable for suitability for industrialized production.
Scheme 3:
Therefore, study simple to operately, yield is high, and cost is low, is suitable for the synthetic method of Dronedarone and the salt thereof of suitability for industrialized production, very significant beyond doubt.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of step few, yield is high, simple to operate, is applicable to the new synthetic method of the suitability for industrialized production of Dronedarone and salt thereof.
One aspect of the present invention relates to a kind of preparation method of Dronedarone hydrochloride, the method comprises that 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone (compd A) reacts the step of directly synthetic Dronedarone hydrochloride with methylsulfonyl chloride, and described reaction does not add catalyzer; Preferably this reaction is carried out in the mixed solvent of a kind of solvent or multi-solvents; Preferably obtain also comprising the further refining step that obtains its sterling after Dronedarone hydrochloride crude product.
The present invention relates to the new preparation method of Dronedarone and salt thereof on the other hand, and described salt is not hydrochloride.The method comprises: first 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone (compd A) reacts synthetic Dronedarone hydrochloride with methylsulfonyl chloride, then through the processing of basic solution, prepares highly purified Dronedarone or is converted into as required pharmaceutically acceptable other salt.The square case 4 of route:
Scheme 4:
In particular, the method for preparing Dronedarone and salt thereof comprises the following steps:
A) 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone (compd A) carries out the synthetic Dronedarone hydrochloride crude product of acylation reaction with methylsulfonyl chloride, and this reaction does not add any catalyzer; Preferably this reaction is carried out in the mixed solvent of a kind of solvent or multi-solvents.
B) described Dronedarone hydrochloride crude product is prepared highly purified Dronedarone or its hydrochloride through the processing of refining or basic solution, or is converted into pharmaceutically acceptable other salt.
The inventor is in the favorite outer discovery of research of acylation reaction; do not needing to add under the condition of any catalyzer; compd A and methylsulfonyl chloride can carry out acylation reaction smoothly; and greatly suppressed (Compound I generation a) of two methylsulfonyl by products; can directly obtain highly purified Dronedarone hydrochloride, thereby obtain preparing the new synthetic method of Dronedarone and salt thereof.
The inventor finds at the solvent of nitrile, ketone, halohydrocarbon, ether or arene or by it in mixed solvent of two or more above-mentioned solvent compositions; do not needing to add under the condition of catalyzer; compd A and methylsulfonyl chloride all can carry out acylation reaction smoothly; and do not need through this loaded down with trivial details purification step of column chromatography and salify operation; directly make highly purified Dronedarone hydrochloride, or certainly Nai Dalong hydrochloride is converted into pharmaceutically other salt of acceptable as required.
The mentioned catalyzer of the present invention refers to 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone is reacted to the catalyzer that has katalysis with methylsulfonyl chloride, sour sorbent material for example, comprise that organic bases is as alkylamine, as triethylamine, dipropyl amine etc.; Mineral alkali is as basic metal and alkaline earth salt thereof, as sodium carbonate, and salt of wormwood, sodium bicarbonate, sodium hydroxide, calcium hydroxide, hydrated barta etc.
Nitrile solvents of the present invention is selected from C
2～C
6fatty nitrile, as acetonitrile, propionitrile, butyronitrile etc., be preferably acetonitrile.
At 0～10 times; preferably 1～8 times; more preferably in 3～6 times of amount acetonitriles; 5-amino-2-butyl-3-of the present invention (4-[3-(dibutylamino) propoxy-] benzoyl) cumarone and 1～5 equivalent; preferred 1.1～3 equivalents; more preferably the methylsulfonyl chloride of 1.2～2.5 equivalents, in room temperature to reflux temperature, preferably reacts under reflux temperature.React complete, in-30～50 ℃, preferably-20～35 ℃, more preferably-15～25 ℃ of crystallizatioies, obtain Dronedarone hydrochloride crude product, then through the processing of refining or alkali aqueous solution, prepare highly purified Dronedarone or its hydrochloride, or be converted into as required pharmaceutically acceptable other salt.
Ketones solvent of the present invention is selected from C
3～C
6aliphatic ketone, be preferably acetone.
At 0～15 times; preferably 4～10 times; more preferably in 5～8 times of amount acetone; 5-amino-2-butyl-3-of the present invention (4-[3-(dibutylamino) propoxy-] benzoyl) cumarone and 1～5 equivalent; preferred 1.5～3.5 equivalents; more preferably the methylsulfonyl chloride of 2～2.5 equivalents, in room temperature to reflux temperature, preferably reacts under reflux temperature.React complete, in-30～55 ℃, preferably-15～40 ℃, more preferably at-10～25 ℃ of crystallizatioies, obtain Dronedarone hydrochloride crude product, then through the processing of refining or alkali aqueous solution, prepare highly purified Dronedarone or its hydrochloride, or be converted into as required pharmaceutically acceptable other salt.
Halogenated hydrocarbon solvent of the present invention is selected from C
1～C
6fatty halohydrocarbon, conventional is methylene dichloride, chloroform, tetracol phenixin etc., is preferably methylene dichloride.
At 0～30 times; preferably 10～25 times; more preferably in 15～20 times of amount methylene dichloride; 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone and 1～15 equivalent; preferred 5～10 equivalents; more preferably the methylsulfonyl chloride of 6～9 equivalents, in room temperature to reflux temperature, preferably reacts under reflux temperature.React complete, with alkaline reagents, process and obtain Dronedarone, described alkaline reagents is alkali metal hydroxide (as sodium hydroxide), alkaline carbonate or alkali metal hydrocarbonate for example, and for example sodium bicarbonate, is preferably sodium bicarbonate.Gained Dronedarone obtains Dronedarone hydrochloride crude product with hydrochloric acid salify, crystallization in acetone, then through the processing of refining or alkali aqueous solution, prepares highly purified Dronedarone or its hydrochloride, or is converted into as required pharmaceutically acceptable other salt.
In ether solvent of the present invention, linear is selected from C
1～C
6aliphatic ether, be preferably glycol dimethyl ether; Cyclic ethers is selected from C
2～C
4fatty cyclic ethers, be preferably tetrahydrofuran (THF).
At 0～15 times; preferably 3～12 times; more preferably in 5～10 times of amount tetrahydrofuran (THF)s; 5-amino-2-butyl-3-of the present invention (4-[3-(dibutylamino) propoxy-] benzoyl) cumarone and 1～8 equivalent; preferred 1.5～5 equivalents; more preferably the methylsulfonyl chloride of 2～3 equivalents, in room temperature to reflux temperature, preferably reacts under reflux temperature.React complete, in-25～50 ℃, preferably-15～40 ℃, more preferably at-10～35 ℃ of crystallizatioies, obtain Dronedarone hydrochloride crude product.Then through the processing of refining or alkali aqueous solution, prepare highly purified Dronedarone or its hydrochloride, or be converted into as required pharmaceutically acceptable other salt.
Aromatic hydrocarbon solvent of the present invention is selected from the conventional replacement in this area or unsubstituted C
6～C
10aromatic hydrocarbons, as toluene, ethylbenzene, isopropyl benzene, be preferably toluene.
The selected mixed solvent of the present invention is similar in nitrile, ketone, halohydrocarbon, ether or aromatic hydrocarbon solvent or the mixed solvent of two or more solvents of inhomogeneity solvent, is preferably acetone-acetonitrile mixed solvent.
The ratio of acetone/acetonitrile of the present invention is 0～5:1; preferred 0.2～3:1; more preferably in the mixed solvent of 0.5～1:1; 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone and 1～5 equivalent; preferred 1.5～4 equivalents; more preferably the methylsulfonyl chloride of 2～3 equivalents, in room temperature to reflux temperature, preferably reacts under reflux temperature.React complete, in-40～50 ℃, preferably-15～40 ℃, more preferably at-10～35 ℃ of crystallizatioies, obtain Dronedarone hydrochloride crude product.Then through the processing of refining or alkali aqueous solution, can prepare highly purified Dronedarone or its hydrochloride, or be converted into as required pharmaceutically acceptable other salt.
The solvent of the refining employing of Dronedarone hydrochloride of the present invention is acetone-water, is preferably 30～5:1 (V/V).
Described Dronedarone hydrochloride is being prepared to Dronedarone or its hydrochloride sterling through the processing of refining or basic solution, or be converted in pharmaceutically acceptable other salt, alkali in selected basic solution is mineral alkali, as sodium hydroxide, sodium carbonate and sodium bicarbonate, be preferably sodium bicarbonate.
In a word; the present invention is as the nitrile solvents of acetonitrile; as the ketones solvent of acetone; in the single solvent of the halohydrocarbon of methylene dichloride or mixed solvent; do not needing to add under the condition of any catalyzer, compd A and methylsulfonyl chloride carry out acylation reaction, do not need through under the complex operations such as column chromatography and salify thereof; processing through refining or basic solution can be prepared highly purified Dronedarone or its hydrochloride, or is converted into pharmaceutically acceptable other salt.
It is few that the inventive method has step, and yield is high, simple to operate, and cost is low, is applicable to the features such as suitability for industrialized production, has significant Social benefit and economic benefit.
Embodiment
Below with reference to specific examples, at length explain the present invention, make the present invention of those skilled in the art comprehend, specific examples is only for technical scheme of the present invention is described, and limits never in any form the present invention.
Unless there is phase counter-statement, in these embodiments, the english abbreviation using has following implication:
HPLC: high pressure liquid chromatography
1h-NMR: hydrogen nuclear magnetic resonance spectrum
MS: mass spectrum
starting material compound A's of the present invention is synthetic
The synthetic reference literature US5 of 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone (compd A), the method preparation described in 223,510A.
Embodiment 1
Step 1) preparation of Dronedarone hydrochloride crude product
In 5L reaction flask, add 480g (1mol) compd A, 1.7L acetonitrile, reflux, drips 100mL (1.29mol) methylsulfonyl chloride/800mL acetonitrile solution, within approximately 25～30 minutes, drips and finishes, reflux 8 hours, naturally cooling, separates out solid next day, filters and obtains 530g Dronedarone hydrochloride crude product.Yield 89.2%, HPLC purity is 99.5%.
Step 2) preparation of Dronedarone hydrochloride
In 5L reaction flask, add 530g Dronedarone hydrochloride crude product, 3.0L acetone and 100mL water, reflux is dissolved, mechanical stirring, water-bath cooling crystallization, approximately 30 minutes, separate out solid, filter, washing with acetone, be dried and obtain 440g title product, yield 83%, 141.5～143 ℃ of fusing points, HPLC purity is 99.8%, MS:[M+H]
+m/e557.50.
Hydrogen nuclear magnetic resonance spectroscopic data and the ownership of table 1. Dronedarone hydrochloride
Embodiment 2
Step 1) preparation of Dronedarone hydrochloride crude product
Method is with implementing step 1 in 1), temperature of reaction is 55～60 ℃, reacts 15 hours, yield 85.3%, HPLC purity is 99.0%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 81%, 141～143 ℃ of fusing points, HPLC purity is 99.5%.
Embodiment 3
Step 1) preparation of Dronedarone hydrochloride crude product
Method is with implementing step 1 in 1), temperature of reaction is 40～45 ℃, reacts 41 hours, yield 82.1%, HPLC purity is 98.3%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 80%, 141～143 ℃ of fusing points, HPLC purity is 99.1%.
Embodiment 4
Step 1) preparation of Dronedarone hydrochloride crude product
In 5L reaction flask, add 530g (1.1mol) compd A and 3L acetone, reflux and drip 200mL (2.58mol) methylsulfonyl chloride/1L acetone soln, within 20 minutes, drip and finish, reflux 6 hours, stirring is spent the night, and separates out from look solid.Dry 473g Dronedarone hydrochloride crude product, the yield 72% of obtaining.HPLC purity is 99.3%.
Step 2) preparation of Dronedarone hydrochloride
In 5L reaction flask, add 470g Dronedarone hydrochloride crude product, 1550mL acetone and 310mL water, reflux is dissolved, mechanical stirring, ice-water bath crystallization approximately 1.5 hours, separates out solid, filter, washing with acetone, the dry title product 399.5g, yield 84% of obtaining, 141.5～143.5 ℃ of fusing points, HPLC purity is 99.5%.
Embodiment 5
Step 1) preparation of Dronedarone hydrochloride crude product
Method is with step 1 in embodiment 4), temperature of reaction is 40～45 ℃, reacts 48 hours, yield 69%, HPLC purity is 98.8%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 83%, 141～143 ℃ of fusing points, HPLC purity is 99.0%.
Embodiment 6
Step 1) preparation of Dronedarone hydrochloride crude product
2.4g (5mmol) compd A is added in 30mL methylene dichloride, and reflux, drips 3mL (38.8mmol) methylsulfonyl chloride/10mL dichloromethane solution, within 20 minutes, drips and finishes, and refluxes 26 hours, detects purity 95%.To neutral, dry with saturated sodium bicarbonate solution washing, filter, be decompressed to dryly, add 6mL acetone, 1mL hydrochloric acid stirring and crystallizing, filters, and dryly obtains 2.1g Dronedarone hydrochloride crude product, yield 70.8%, HPLC purity is 99%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 81%, 141.5～143.5 ℃ of fusing points, HPLC purity is 99.5%.
Embodiment 7
Step 1) preparation of Dronedarone hydrochloride crude product
In 500mL reaction flask, add 53g (0.11mol) compd A and 350mL tetrahydrofuran (THF), reflux and drip 20mL (0.26mol) methylsulfonyl chloride/40mL tetrahydrofuran solution, within 20 minutes, drip and finish, reflux 9 hours, stirring is spent the night, and separates out from look solid.Be dried and obtain 56.4g Dronedarone hydrochloride crude product, yield 86%, HPLC purity is 98.8%.
Step 2) preparation of Dronedarone hydrochloride
In 500mL reaction flask, add 55g Dronedarone hydrochloride crude product, 225mL acetone and 22.5mL water, reflux is dissolved, mechanical stirring, ice-water bath crystallization approximately 1 hour, separates out solid, filter, washing with acetone, the dry 45.1g title product, yield 82% of obtaining, 141.5～143.5 ℃ of fusing points, HPLC purity is 99.1%.
Embodiment 8
Step 1) preparation of Dronedarone hydrochloride crude product
In 5L reaction flask, add 64g (0.13mol) compd A, 1L acetone and 1L acetonitrile, reflux, drips 26mL (0.34mol) methylsulfonyl chloride/104mL acetonitrile solution, within approximately 25～30 minutes, drips and finishes, reflux 16 hours, naturally cooling, separates out solid next day, filters and obtains 68g Dronedarone hydrochloride crude product.Yield 88.3%, HPLC purity is 99.1%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 82.5%, 141.5～143 ℃ of fusing points, HPLC purity is 99.4%.
Embodiment 9
Step 1) preparation of Dronedarone hydrochloride crude product
Method is with implementing step 1 in 7), temperature of reaction is 40～45 ℃, reacts 36 hours yields 86.1%, HPLC purity is 98.8%.
Step 2) preparation of Dronedarone hydrochloride
Method is with implementing step 2 in 1), yield 82.5%, 141.5～143 ℃ of fusing points, HPLC purity is 99.2%.
Embodiment 10
Step 1) preparation of Dronedarone
5.93g (0.01mol) the Dronedarone hydrochloride of gained in embodiment 1 is dissolved in 40mL methylene dichloride, add saturated sodium bicarbonate solution to regulate pH to neutral, separate organic phase, with saturated sodium bicarbonate solution 10mL * 2, wash, add anhydrous sodium sulfate drying, filter, evaporated under reduced pressure, obtains 5.61g oily matter.
Step 2), the preparation of Dronedarone vitriol
By step 1) gained oily matter adds in 12mL acetone and dissolves, add 2mL water, in 10～15 ℃ of 3mL acetone solns that slowly drip the 1.1mL vitriol oil, within approximately 20 minutes, drip and finish, rise to 52 ℃ and stir 1 hour, under ice-water bath, stirring and crystallizing is 3.5 hours, filters, in 50 ℃ of vacuum-dryings, obtain 5.5g product, yield 84% (in Dronedarone hydrochloride).HPLC purity is 99.85%.
Embodiment 11
Step 1), the preparation of Dronedarone
Method is with implementing step 1 in 10).
Step 2), the preparation of Dronedarone mesylate
Method is with step 2 in embodiment), difference is to use 1.5g methylsulfonic acid (99%), yield 76%, HPLC purity is 99.83%.
Embodiment 12
Step 1) preparation of Dronedarone hydrochloride crude product
In 100mL reaction flask, add 15g (0.03mol) compd A, 15mL (0.19mol) methylsulfonyl chloride, be warming up to 80 ℃, insulation reaction 5.5 hours, removes unreacted methylsulfonyl chloride under reduced pressure, add acetonitrile 100mL to dissolve, naturally cooling, separates out solid next day, filters and obtains 13.5g Dronedarone hydrochloride crude product.Yield 72.5%, HPLC purity is 97.5%.
Step 2) preparation of Dronedarone hydrochloride
Method is with step 2 in embodiment 1), yield 78.5%, 140.5～142.5 ℃ of fusing points, HPLC purity is 98.9%.
Claims (14)
1. a method of preparing Dronedarone hydrochloride, is characterized in that, the method comprises the steps:
5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone reacts with methylsulfonyl chloride and obtains Dronedarone hydrochloride, and described reaction does not add catalyzer.
2. the method for preparing Dronedarone hydrochloride according to claim 1; it is characterized in that; described 5-amino-2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl) cumarone carries out with reacting in the mixed solvent of a kind of solvent or multi-solvents of methylsulfonyl chloride; described solvent is selected from nitrile, ketone, halohydrocarbon or ether solvent, and wherein said nitrile solvents is selected from C
2～C
6fatty nitrile; Described ketones solvent is selected from C
3～C
6aliphatic ketone; Described halogenated hydrocarbon solvent is selected from C
1～C
6fatty halohydrocarbon; Described ether solvent is tetrahydrofuran (THF).
3. the method for preparing Dronedarone hydrochloride according to claim 2, is characterized in that, two or more solvent compositions of described mixed solvent similar or inhomogeneity solvent in nitrile, ketone, halohydrocarbon or ether.
4. according to the method for preparing Dronedarone hydrochloride described in claim 2 or 3, it is characterized in that, described nitrile solvents is acetonitrile.
5. according to the method for preparing Dronedarone hydrochloride described in claim 2 or 3, it is characterized in that, described ketones solvent is acetone.
6. according to the method for preparing Dronedarone hydrochloride described in claim 2 or 3, it is characterized in that, described halogenated hydrocarbon solvent is methylene dichloride.
7. according to the method for preparing Dronedarone hydrochloride described in claim 1-3 any one, it is characterized in that, the method further comprises the refining step of described Dronedarone hydrochloride.
8. the method for preparing Dronedarone hydrochloride according to claim 7, is characterized in that, the solvent of the refining employing of Dronedarone hydrochloride is acetone-water.
9. the method for preparing Dronedarone hydrochloride described in 8 as requested, is characterized in that, the volume ratio of described acetone-water is 30:1～5:1.
10. a method of preparing Dronedarone and salt thereof, is characterized in that, comprises the step of preparing Dronedarone hydrochloride described in claim 1-9 any one.
11. methods of preparing Dronedarone and salt thereof according to claim 10, characterized by further comprising Dronedarone hydrochloride is prepared to Dronedarone or is further converted to the step of pharmaceutically acceptable other salt through the processing of basic solution.
12. methods of preparing Dronedarone and salt thereof according to claim 11, is characterized in that, the alkali in described basic solution is mineral alkali.
13. methods of preparing Dronedarone and salt thereof according to claim 12, is characterized in that, described mineral alkali is selected from sodium hydroxide, sodium carbonate or sodium bicarbonate.
14. methods of preparing Dronedarone and salt thereof according to claim 13, is characterized in that, described mineral alkali is sodium bicarbonate.
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|---|---|---|---|
| CN201180003259.6A CN102471302B (en) | 2010-06-09 | 2011-06-03 | Preparation process of dronedarone and its salts |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101957337A CN102276561A (en) | 2010-06-09 | 2010-06-09 | Preparation method of Dronedarone and its salt |
| CN201010195733.7 | 2010-06-09 | ||
| CN201180003259.6A CN102471302B (en) | 2010-06-09 | 2011-06-03 | Preparation process of dronedarone and its salts |
| PCT/CN2011/075255 WO2011153923A1 (en) | 2010-06-09 | 2011-06-03 | Preparation process of dronedarone and its salts |
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| CN102471302B true CN102471302B (en) | 2014-03-26 |
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| CN201180003259.6A Expired - Fee Related CN102471302B (en) | 2010-06-09 | 2011-06-03 | Preparation process of dronedarone and its salts |
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|---|---|
| US (1) | US8481763B2 (en) |
| EP (1) | EP2581369A4 (en) |
| JP (1) | JP5873484B2 (en) |
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| WO (1) | WO2011153923A1 (en) |
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| US20120108828A1 (en) * | 2010-09-09 | 2012-05-03 | USV Limited, B.S.D. Marg | Synthesis of dronedarone and salts thereof |
| EP2447256A1 (en) * | 2010-10-21 | 2012-05-02 | Laboratorios Lesvi, S.L. | Process for obtaining dronedarone |
| WO2012120544A2 (en) * | 2011-03-10 | 2012-09-13 | Sun Pharmaceutical Industries Ltd. | PROCESS FOR N-[2-n-BUTYL-3-[4-[3-(DI-n-BUTYLAMINO) PROPOXY]ENZOYL]BENZOFURAN-5-YL]METHANESULFONAMIDE HYDROCHLORIDE |
| WO2012153225A1 (en) * | 2011-05-09 | 2012-11-15 | Alembic Pharmaceuticals Limited | Improved processes for obtaining high purity of dronedarone hydrochloride |
| CN103044369A (en) * | 2012-12-21 | 2013-04-17 | 北京华禧联合科技发展有限公司 | Refining method for dronedarone hydrochloride |
| WO2014203058A1 (en) * | 2013-06-17 | 2014-12-24 | Aurobindo Pharma Limited | An improved process for preparing benzofuran compound |
| CN107880003A (en) * | 2016-09-30 | 2018-04-06 | 北京新领先医药科技发展有限公司 | A kind of new method of refined dronedarone hydrochloride |
| CN112442003B (en) * | 2020-12-17 | 2022-04-19 | 南京方生和医药科技有限公司 | Dronedarone intermediate impurity and preparation method thereof |
Citations (4)
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|---|---|---|---|---|
| EP0471609A1 (en) * | 1990-08-06 | 1992-02-19 | Sanofi | Benzofuran Derivatives, Benzothiophenes, Indoles or Indolizines, Process for Production and Compositions containing them |
| CN1306000A (en) * | 2000-01-17 | 2001-08-01 | 科莱恩(法国)公司 | 3-(1-hydroxy-amylene)-5-nitro-3h-benzfuran-2-one, its prepn. method and use |
| CN101153012A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Novel method of producing dronedarone key intermediate |
| WO2008152217A2 (en) * | 2007-04-27 | 2008-12-18 | Finorga | Process for preparing 2-(n-butyl)-5-nitrobenzofuran |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US522351A (en) | 1894-07-03 | phillips | ||
| IL146389A0 (en) | 2001-11-08 | 2002-07-25 | Isp Finetech Ltd | Process for the preparation of dronedarone |
| FR2833262A1 (en) | 2001-12-06 | 2003-06-13 | Rhodia Chimie Sa | PROCESS FOR MONOSULFONYLATION OF AN AMINOBENZOFURANNE OR AMINOBENZOTHIOPHENE COMPOUND |
-
2010
- 2010-06-09 CN CN2010101957337A patent/CN102276561A/en active Pending
-
2011
- 2011-06-03 US US13/701,642 patent/US8481763B2/en active Active
- 2011-06-03 WO PCT/CN2011/075255 patent/WO2011153923A1/en active Application Filing
- 2011-06-03 CN CN201180003259.6A patent/CN102471302B/en not_active Expired - Fee Related
- 2011-06-03 JP JP2013513534A patent/JP5873484B2/en not_active Expired - Fee Related
- 2011-06-03 EP EP11791914.2A patent/EP2581369A4/en not_active Withdrawn
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| EP0471609A1 (en) * | 1990-08-06 | 1992-02-19 | Sanofi | Benzofuran Derivatives, Benzothiophenes, Indoles or Indolizines, Process for Production and Compositions containing them |
| CN1306000A (en) * | 2000-01-17 | 2001-08-01 | 科莱恩(法国)公司 | 3-(1-hydroxy-amylene)-5-nitro-3h-benzfuran-2-one, its prepn. method and use |
| CN101153012A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Novel method of producing dronedarone key intermediate |
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| Publication number | Publication date |
|---|---|
| CN102276561A (en) | 2011-12-14 |
| US20130072697A1 (en) | 2013-03-21 |
| EP2581369A1 (en) | 2013-04-17 |
| CN102471302A (en) | 2012-05-23 |
| WO2011153923A1 (en) | 2011-12-15 |
| EP2581369A4 (en) | 2014-01-22 |
| JP5873484B2 (en) | 2016-03-01 |
| US8481763B2 (en) | 2013-07-09 |
| JP2013530959A (en) | 2013-08-01 |
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